Process for the preparation of 3-fluoro-d-alanine

ABSTRACT

Organic compounds having at least one replaceable hydrogen atom are fluorinated in the liquid or solid state by treatment with fluoroxyperfluoroalkanes or fluoroxypentafluorosulfur under the influence of a free radical initiator.

United States Patent Kollonitsch Oct. 1, 1974 1 PROCESS FOR THE PREPARATION OF F R NPATENT RA L 3 FLUORO D ALANINE 0 1510 S 0 PP 1CAT1ONS 30,152 12/1964 Japan 260/534 C [75] Inventor: Janos Kollonitsch, Westfield, NJ. [73] Assignee: Merck & Co., Inc., Rahway, NJ. OTHER PUBLICATIONS Borton et al., Chemical Communications, (1969), [22] Filed. Apr. 18, 1972 p g 8O4 806. [21] Appl. No.: 245,288

Related US. Application Data Primary ExaminerHoward S. Williams [63] Continuation of Ser. No. 60,645, Aug. 3, 1970,

abandoned.

[57] ABSTRACT [52] 158 204/158 260/534 C Organic compounds having at least one replaceable [51] m B013 1/10 C07c 101/08 C07: 101/19 hydrogen atom are fluorinated in the liquid or solid [58] Field of Search 204/158 HA, 158 HE, State by treatment with fluoroxyperfluoroalkanes or 260/534 534 C fluoroxypentafluorosulfur under the influence of a References Cited free radical mmator.

UNITED STATES PATENTS 6 Claims, N0 Drawings 3,151,051 9/1964 Braid et al. 204/158 PROCESS For THE PREPARATION OF S-FLUORO-D-ALANINE This is a continuation of application Ser. No. 60,645, filed Aug. 3, 1970, now abandoned.

This invention relates to a novel process for the fluorination of organic compounds. In particular it relates to the fluorination of organic compounds in the liquid or solid phase with fluoroxyperfluoroalkanes or fluoroxypentafluorosulfur. Still more particularly it relates to monoor poly-fluorination of organic compounds with fluoroxyperfluoroalkanes or fluoroxypentafluorosulfur under conditions conducive to the formation of free radicals.

The novel process of this invention can be represented by the following equation:

R H, R H, ,F,.

free radical initiator RH, represents an organic molecule having x replaceable hydrogens linked to carbon. The organic molecule substrate can be virtually any such entity which is subject to free radical substitution and includes such as: (l) monoand polynuclear carbocyclic aromatic compounds such as benzenes, naphthalenes, phenanthrenes, anthracenes, fluoroanthenes, pyrenes, chrysenes, indenes, fluorenes, n'aphthacenes and the like, either unsubstituted or substituted with such as halo, lower alkyl, lower alkoxy, amino, or monoor di-(lower alkyl)amino; (2) monoor polynuclear alicyclic compounds, such as the monocycloalkanes, polyand perhydronaphthalenes, polyand perhydrophenanthrenes, adamantane and the like, either unsubstituted or substituted with such as lower alkyl, amino, carboxyl, nitro, halo or lower alkoxy; (3) alkanes and alkenes either unsubstituted or substituted with such as halo, or amino; (4) amino acids, either cyclic or acyclic, and either basic or acidic; (5) fatty acids and derivatives such as amides, either unsubstituted or substituted with such as halo; (6) polymers such as polycaprolactam, polyethylene, polystyrene and the like; (7) heterocycles, either substituted or unsubstituted such as cinnolines, phthalazines, quinazolines, quinoxalines, acridines, phenanthridines, phenantholines, phenazines, pyridazines, imidazoles, pyrazoles, indoles, triazoles, indazoles, pyrroles, furans, thiophenes, piperidines, piperazines, pyrrolidines, azetidines, and the like.

R,-OF represents a fluoroxyperfluoroalkane wherein the alkyl group is of one to about five cabon atoms, such as fluoroxytrifluoromethane, fluoroxyperfluoroethane, 1- or 2-fluoroxyperfluoropropane, or 2- fluoroxyperfluoro-2-methyl-propane.

Prior to this invention the scope and utility of known methods for substitutive fluorination of organic compounds in the sense of the equation:

were very limited. The most important methods available for the above type of transformation were (1) reaction with elementary fluorine, (2) electrolytic fluorination in liquid hydrogen fluoride, (3) reaction with high valency oxidative metallic fluorides such as cobalt trifluoride, (4) reaction with perchloryl fluoride, and (5) fluorination with fluoroxyperfluoroalkanes.

The main limitations with methods (I), (2) and (3) are that they usually result in mixtures of polyfluorinated compounds even in the case of substrates with simple structures. With more complex substrates, extensive degradation and carbon skeletal rearrangements often occur, thus severely limiting the yield and predictability of any individual product. In contrast, method (4), employing perchloryl fluoride, allows more selective fluorination, and does not generally cause degradation of the substrate,'but is only effective with especially reactive substrates such as activated methylene groups.

Method (5), fluorination with fluoroxyperfluoroalkanes has been reported in the prior art. D. H. R. Barton et al., in Chemical Communications, 1968, 804, 806; 1969, 227 published on the fluorination of alkenes and aromatic compounds. The reactions described therein were electrophilic, proceeded in the dark, i.e., in the absence of irradiation, and required suitably activated aromatic substrates. Allison et al. in J I} Amer. Chem. Soc., 81, 1089-1091 (1959) also reported on Reactions of Trifluormethyl l-lypofluorite with Organic Compounds. The reactions described were conducted at room temperature in the gas phase and were spontaneous or initiated with ultraviolet light or by a spark. In the case of alkenes, the fluoroxytrifluoromethane added across the double bond; benzene exploded to give a very low yield of fluorobenzene; and alkanes yielded the entire spectrum of fluorinated alkanes in low yield.

Surprisingly it has now been found that the limited usefulness of fluoroxyperfluoroalkanes and fluoroxypentafluorosulfur can be greatly extended by conducting the reaction in the liquid or solid phase under conditionsconducive to the formation of free radicals.

The novel process of this invention comprises treating the substrate with a fluoroxyperfluoroalkane or fluoroxypentafluorosulfur under the influence of a free radical initiator such as light which includes ultraviolet light, ionizing radiations such as y-rays or microwaves, or chemical chain initiators such as azo compounds, for

example, azo-bis-isobutyronitrile or combinations of such free radical initiators. The preferred mode of operation is to dissolve the substrate in a suitable solvent which is inert to the fluorination reaction such as fluorotrichloromethane or other similar halogenated alkane, or a strong acid such as liquid hydrogen fluoride, fluorosulfonic' acid, trifluoroacetic acid or sulfuric acid; expose the solution to the free radical initiator; with vigorous stirring and maintenance of temperature, admit the required amount of the fluoroxy reagent slowly to the reaction mixture; and continue agitation and irradiation until reaction is complete.

Use of one of the strong acids as solvent is particularly advantageous in, but not limited to, those instances wherein the substrate carries one or more basic functional groups such as amino, or alcohol or the like. In addition, if desired, a strong acid can be employed in combination with one of the non-acidic solvents.

Because of the low boiling point of the reagents it is convenient to conduct the reaction at temperatures as low as C. in which case the reaction proceeds at atmospheric pressure.

A suitable reaction vessel for atmospheric pressure reactions is one machined from a Kel-F rod equipped with an ultraviolet-transparent window. Alternatively the reaction can be conducted in a pressure vessel such as a Hastelloy bomb or a steel bomb with a platinum lining, in which case higher temperatures, for instance up to about 100 C. can be employed. In such case the use of y-rays or x-rays as free radical initiator is convenient, as these high energy rays penetrate the wall of the reactor.

The above described process can be performed by conventional batch techniques, or alternatively it can be run in a continuous manner in a tubular reactor either with or without packing such as Raschig rings, saddles or the like through which the substrate or its solution and the fluorinating agent are pumped, preferably in a countercurrent fashion while being exposed to radical generating radiation. This method of operation is particularly advantageous in cases where the particular substrate is subject to reaction with the fluoroxy compound even in the absence of radical generating conditions. In this case, by employing the above continuous technique it becomes possible to accelerate the radical type reaction, while leaving unchanged the rate of the non-radical reaction, thus raising the yield of the product formed by radical reaction.

A convenient source of radiation for radical generation was found to be a Hanovia mercury-xenon arc lamp No. 9778-1, run by a 1,000 W. power supply. The lamp was mounted in a Schoeffel 1H IN Projector equipped with a quartz condensor lens and a heat filter (water).

the novel process of this invention provides a convenient route to a large variety of organic fluorine compounds. Such compounds are known to have wide ranging utility as, for example, solvents, intermediates in organic synthesis, insecticides, plant growth regulators, herbicides, refrigerants, lubricants,pharmaceuticals and so on. 5-Fluoro-2-methyl-l-(pmethylsulfinylbenzylidene)-inden-3-acetic acid and 4- (2-pheny-l,1,2,2-tetrafluoroethyl)-a,a-dimethylbenzylamine prepared by the novel process of this invention have utility as antiinflamatory and antiarrhythmic agents respectively.

In addition the novel process provides a useful route to many new compositions of matter such as 3-fluoro- D-alanine, a compound displaying antibacterial activity against several classes of pathogenic micro-organisms, 3-fluoro-L-azetidine-Z-carboxylic acid, 3-, and 4-fluoro- 1 -aminoadamantane, difluoro-eaminocaprolactam, trifluoro-e-aminocaprolactam, fluorinated polycaprolactam containing 1.25 and 2.9 atoms of fluorine per unit mole, and fluorinated polyethylene.

EXAMPLE 1 Fluorination of benzene with fluoroxytrifluoromethane with the reactor immersed in a dry-ice-acetone bath, and with vigorous stirring and irradiation with ultraviolet light, 2.7 g. of fluoroxytrifluoromethane gas was introduced over a period of one hour to a solution of 2.03 g. of benzene in 80 ml. of fluorotrichloromethane. After an additional hour of irradiation under similar conditions, the mixture was subjected to separation by preparative gas-liquid chromatography on a column filled with percent QF-l (Dow-Corning brand of methylsilicone) on Gas-chrom Z (silylated diatomaceous earth) at 90 C. The yield of fluorobenzene was 0.87 g. (65 percent of theory, based on recovery of 0.93 g. of benzene).

EXAMPLE 2 Fluorination of benzene with fluoroxypentafluorosulfur Benzene (0.78 g., 0.01 mole), dissolved in 55 ml. of fluorotrichloromethane was ultraviolet irradiated and 3.24 g. fluoroxypentafluorosulfur (0.02 mole) was passed into it in a period of 20 min, while being stirred in a dry-ice-acetone bath. After 1 hour further ultraviolet irradiation, the solvent was distilled off and the residue analyzed by glc-mass spectrometry, to indicate the formation of fluorobenzene as the principal reaction product.

Employing the procedure of Example 1 or 2, but substituting for the benzene employed therein an equivalent amount of the aromatic starting materials shown in Table I, there is produced the fluoro-aromatic products, also shown in Table 1.

TABLE I Example Starting Material Product 3 naphthalene l-fluoronaphthalene 2-fluoronaphthalene 4 anthracene mixture of fluoroanthracenes 5 indene 2-fluor0indene 3-fluoroindene 6 phenanthrene mixture of fluorophenanthrenes 7 fluorene mixture of fluorofluorenes 8 N-acetyl-afluoro-Nacetyl-anaphthylamine naphthylamine fluorination of 4,4-bis-acetamino-diphenylsulfone 4,4'-Bis-acetamino-diphenylsulfone (3.4 g.) was dissolved in 32 ml. of trifluoroacetic acid, cooled to 12 C., then under stirring and ultraviolet irradiation 2.1 g. of fluoroxytrifluoromethane was introduced over about 1 hour and irradiation was continued for another 2 hours. Another 1 g. quantity of fluoroxytrifluoromethane was added over about 1 hour, followed by an irradiation period of 2% hours. The temperature was kept at 100 C.

The residue obtained after evaporation of trifluoroacetic acid in vacuo was treated with water and sodium bicarbonate solution, washed with water and dried in vacuo to give a light-tan crystalline product, which according to glc-mass spectrometry, represented a 1:1 mixture of monofluoro and difluoro-4,4-bisacetamino-diphenylsulfone.

EXAMPLE l3 Fluorination of Anisole Anisole (1.62 g., 0.015 mole), dissolved in 50 ml. of fluorotrichloromethane was stirred and irradiated with ultraviolet light at about C., while 1.14 g. (0.01 1 mole) of fluoroxytrifluoromethane gas was passed in over 1/2 hour. The irradiation and stirring were continued for another 1/2 hours. The solvent was evaporated, and the residual clear oil was analyzed by gas-liquid chromatography and mass spectrometry. The product consisted of 58 percent of anisole, 38 percent of ofluoroanisole and 4 percent of a mixture of m-and pfluoroanisole. (Gas-liquid chromatography was on foot x 1/4 inch 20 percent QF-l on 80/100 mesh Gas- Chrom Z; column 150 C., detector 260 C., injection 175 C.).

EXAMPLE 14 Fluorination of Toluene Into a solution of toluene (1.38 g., 0.015 mole), dissolved in 50 ml. of fluorotrichloromethane, 1.9 g. of fluroxytrifluoromethane (0.019 mole) was passed in during a 1/2 hour period while being stirred and ultraviolet irradiated under cooling in a dry-ice-acetone bath. The ultraviolet irradiation and stirring were continued for another 40 min. Gas-liquid chromatographic analysis, combined with mass spectrometry, indicated that o-fluorotoluene and benzylfluoride were the main reaction products.

EXAMPLE 15 5 -Fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)inden-3-acetic acid Step A: 2-Methylinden-3-acetic acid Z-Methylindanone (0.112 mole), cyanacetic acid (10.5 g., 0.123 mole), acetic acid (6.6 g.), and ammonium acetate (1.7 g.) in dry toluene (15.5 ml.) was refluxed with stirring for 21 hrs., as the liberated water was collected in a Dean Stark Trap. The toluene was concentrated and the residue dissolved in 60 ml. of hot ethanol and 14 ml. of 2.2 N aqueous potassium hydroxide solution. 22 g. Of 85 percent KOI-l in 150 ml. of water was added and the mixture refluxed for 13 hr. under N The ethanol was removed under vacuum, 500 ml. water added, the aqueous solution washed well with ether and then boiled with charcoal. The aqueous filtrate was acidified to pH 2 with 50 percent hydrochloric acid, cooled and the precipitate of 2-methylinden-3-acetic acid was collected. Step 13: Z-Methyl- 1 -(p-methylthiobenzylidene)inden-3- acetic acid 2-Methylinden-3-acetic acid (0.072 mole) p-methylthiobenzaldehyde (14.0 g., 0.091 mole) and sodium methoxide (13.0 g., 0.24 mole) were heated in methanol (200 ml.) at 60 C. under nitrogen with stirring for 6 hr. After cooling, the reaction mixture was poured into 750 ml. of ice-water, acidified with 2.5N hydrochloric acid and the collected solid triturated with a little ethyl ether. The crude 2-methyl-1-(pmethylthiobenzylidene)inden-3-acetic acid was collected. Step C: Z-Methyl-1-(p-methylsulfinylbenzylidene)inden-3-acetic acid To a solution of 2-methyl-1-(pmethylthiobenzylidene)inden-3-acetic acid (0.01 mole) in a mixture of methanol (250 ml.) and acetone (100 ml.) was added a solution of sodium periodate (3.8 g., 0.018 mole) in water (50 ml.) with stirring.

Water (450 ml.) was added after 18 hr. and the organic solvents removed under vacuum below 30 C. The precipitated product,2-methyl-l-(p-methylsulfinylbenzylidene) inden-3-acetic acid, was filtered, dried and recrystallized from ethyl acetate to give 3.0 g. 2-methyl-1-(p-methylsulfinylbenzylidene)inden-3- acetic acid.

Step D: 5-Fluoro-2-methyll -(pmethylsulfinylbenzylidene)-inden-3-acetic acid 2-Methyll -(p-methylsu1finylbenzylidene)inden-3- acetic acid (2.25 g.) dissolved in ml. of fluorotrichloromethane was ultraviolet irradiated and stirred at -l5 C. for 80 min.; meanwhile 1.2 g. of fluoroxytrifluoromethane was passed in. The residue obtained after evaporation of the solvent was subjected to chromatography on a silica gel column, to give 5-fluoro-2- methyl-1-(p-methylsulfinylbenzylidene)inden-3-acetic acid, m.p. 188-189 C.

EXAMPLE l6 clohexane to be the major product.

EXAMPLE 17 Fluorination of Cyclohexane with Fluoroxyperfluoroethane Cyclohexane (0.84 g., 0.01 mole) is dissolved in 50 ml. of fluorotrichloromethane, then while being ultraviolet irradiated and vigorously stirred, 1.5 g. of fluoroxypentafluoroethane is passed in during a period of 2 hours while the reaction mixture is cooled in a dry-iceacetone bath. The solvent is evaporated by a stream of nitrogen gas and the residue distilled in vacuo at 210 mm Hg pressure to give fluorocyclohexane.

Employing the procedure of Example 16 or 17, but substituting for the Cyclohexane employed therein, an equivalent amount of the cycloalkanes shown in Table 11, there is produced thefluorocycloalkane products, also shown in Table 11.

Fluorination of l-amino-adamantane with fluoroxytrifluoromethane Into a solution of l-amino-adamantane hydrochloride (1.88 g., 0.01 mole) in 40 ml. of liquid HF, 1.14 g. (0.011 mole) of fluoroxytrifluoromethane gas was introduced over a 30 min. period, under ultraviolet irradiation, while vigorously stirred and cooled in a dryice-acetone bath. After a further 30 min. of irradiation the solvent was blown off with a stream of nitrogen. The residue was dissolved in water, the pH was adjusted to pH 9 by addition of l-N sodium hydroxide solution, the separated solid was extracted with diethyl ether (2 x 20 ml.), the combined extracts were dried overnight and evaporated to dryness, to give a colorless solid, which according to combined gasliquid chromatography and mass spectrometric analysis consisted of, besides some unchanged starting material, a mixture of fluoro-lamino-adamantanes. NMR spectroscopy indicated the latter compounds to be 3-fluoro-1-aminoadamantane and 4-fluoro-l-amino-adamantane. For preparative separation, the mixture was subjected to ion-exchange chromatography on Dowex 50-x-8 resin (a polystyrene nuclear sulfonic acid resin sold by Dow Chemical Co., Midland, Mich.) by elution with 4N hydrochloric acid.

EXAMPLE 27 2-Fluoroethylamine Ethylamine hydrochloride (0.82 g., 0.01 mole) is dissolved in 35 ml. of liquid HF, then while irradiated by ultraviolet light and stirred under cooling in a dry-iceacetone bath, 2.5 g. of fluoroxytrifluoromethane is passed into it over a period of 2 /2 hours. This is followed by 1 /2 hours more ultraviolet irradiation under similar conditions. The HF solvent is then distilled off and the residue analyzed by pmr and F nmr spectroscopy, to indicate that it represents about a 2:1 mixture of 2-fluoroethylamine and ethylamine, respectively (in the form of their hydrofluorides).

EXAMPLE 28 2,2-Difluoroethylamine Employing the procedure substantially as described in Example 27, but by employing g. of fluoroxytrifluoromethane instead of 2.5 g. and double the reaction time there is produced 2,2-difluoroethylamine.

EXAMPLE 29 2,2,2-Trifluoroethylamine By employing the procedure substantially as described in Example 28 but introducing 9.5 g. of fluoroxytrifluoromethane over 6 hours, followed by 1 /2 hours of ultraviolet irradiation, 2,2,2-trifluoroethylamine is obtained as the main reaction product.

EXAMPLE 30 Fluorination of n-butylamine Butylamine hydrochloride (1.1 g., 0.01 mole) was dissolved in 40 ml. of liquid HF, then under vigorous stirring at -78 C. and irradiation with ultraviolet light, 3.8 g. of fluoroxytrifluoromethane gas was passed into it, in 3 portions. First, 0.95 g. of fluoroxytrifluoromethane was added in 30 min., followed by an additional hour of ultraviolet irradiation; then with the same timing a second 0.95 g. portion of reagent, finally a 1.9 g. portion of reagent was added. The HF solvent was removed by a nitrogen gas stream and the residue was analyzed by elementary analysis and pmr spectrum, to indicate the main product of the reaction to be 3,3- difluorobutylamine.2 HF.

EXAMPLE 31 5-Fluoro-L-isoleucine L-lsoleucine (1.31 g., 0.01 mole) was dissolved in 40 ml. of liquid hydrogen fluoride. After cooling to, and while maintaining at 78 C., 1.04 g. of fluoroxytrifluoromethane was added over minutes with vigorous agitation and irradiation with ultraviolet light. The solvent was evaporated at ambient temperature by passing nitrogen gas through the reaction mixture. As determined by proton magnetic resonance, and fluorine magnetic resonance, the major product was Sfluoro-L-isoleucine.

The identity of the product was further proved by conversion to trans3-methyl-L-proline by dissolving the product in 10 ml. of water, adjusting to pH 10 with 2.5 N sodium hydroxide solution, and allowing to stand overnight at ambient temperature. Analysis by Spinco- Beckman amino acid analysis indicated the presence of 0.503 g. of trans-3-methyl-L-proline (39 percent of theory).

EXAMPLE 32 3-Fluoro-D-alanine Into a solution of 1.822 g. of D(-) alanine in 45 ml. of liquid HF, 0.6 g. of fluoroxytrifluoromethane gas was passed over a period of about 1 hour while being magnetically stirred, cooled in a dry-ice-acetone bath and irradiated by ultraviolet light. After 80 minutes further I ultraviolet irradiation, 2g. more of fluoroxytrifluoromethane gas was passed in while being ultraviolet irradiated over one and a half hours, followed by another 1 hour ultraviolet irradiation.

The solvent was removed by blowing through it a stream of nitrogen gas. The residue was dissolved in ice-water and a sample of it was analyzed in the Spinco- Beckman amino acid analyzer, indicating a 41 percent yield of 3-fluoro-D-alanine, and 32 percent of unreacted starting material. For isolation, the mixture was chromatographed on Dowex 50 x 8 cation exchange resin (H form) (a polystyrene nuclear sulfonic acid resin sold by Dow Chemical Co., Midland, Michigan). For elution, 2N HCl was employed. From the appropriate fractions, by evaporation in vacuo, pure 3-fluoro-D- alanine hydrochloride was obtained. 3-Fluoro-D- alanine was liberated from the hydrochloride in waterpyridine-isopropanol mixture, m.p. 166168 C. (dec); [11], 9.3 (lN-HCI).

EXAMPLE 33 3-Fluor0L-Azetidine-2-carboxylic acid Into a solution of 3.92 g. (0.039 mole) of L-azetidine- 2-carboxylic acid in 60 ml. of liquid HF, 2.9 g. of fluoroxytrifluoromethane gas was introduced while being ultraviolet irradiated and stirred under cooling in a dry ice-acetone bath. The addition took about min. The ultraviolet irradiation and stirring were continued for another 45 min., then 1.7 g. more of fluoroxytrifluoromethane was added in about min., followed again by about 100 min. more of ultraviolet irradiation and stirring. Then 1.1 g. more of fluoroxytrifluoromethane was introduced over a 1 hour period, followed by about 30 min. additional ultraviolet irradiation. A fourth portion of reagent (2.2 g.) was introduced over a 1 hour period followed by 30 min. irradiation. Finally 1.5 g. of reagent was added in 30 min., followed by a similar period of ultraviolet irradiation. The solvent was then evaporated at room temperature. The

, residue was quenched in ice-water, evaporated in chromatographed on about 1.4 l of Dowex 50 x 8 resin column (analyt. grade, 200-400 mesh). Eluants: 3 l of N/L aq. HCl (discarded) followed by 2.4 l of 2N aq. HCl (20 ml. fractions). Fractions No. 50-70 of the 2N HCl eluants contained the desired product. These were combined and evaporated to dryness in vacuo at room temperature. The residue was mixed with 1 ml. of water, 2 ml. of pyridine and 6 ml. of isopropanol to give 2.4 g. of colorless crystals of 3-fluoro-L-azetidine-2- carboxylic acid, m.p. 197 C. (dec.). Its assigned structure was confirmed by pmr spectroscopy and analysis, c l-l NO F,

Cale-C, 40.3; H, 5.1; N, 11.8; F, 16.00 percent FoundC, 39.9; H, 5.0; N, 11.9; F, 16.2.

Employing the procedure substantially as described in Example 31, 32 or 33, but substituting for the amino acids used therein, an equivalent amount of the amino acid starting materials depicted in Table 111, there are produced the fluorinated amino acids also described in Table 111.

"by doubling the amount of reagent and reaction times by tripling the amount of reagent and reaction times EXAMPLE 42 Fluoro-e-aminocaprolactam e-Aminocaprolactam (2.26 g., 0.02 mole) is dissolved in 60 ml. of liquid HF. Fluoroxytrifluoromethane (10.4 g., 0.1 mole) is passed into the solution under ultraviolet irradiation over 5 /2 hours, while kept under vigorour stirring in a dry-ice-acetone cooling bath. After 1% hours more ultraviolet irradiation under similar conditions, the solvent is removed by distillation. The residue is quenched with ice and water and extracted three times with ethyl acetate. The combined extracts are washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness, to give a mixture of C-fluorinated caprolactams, with the main components being difluorocaprolactam and trifluoro-caprolactam.

EXAMPLE 43 Fluoro-polycaprolactam 1.13 g. of Polycaprolactam (nylon-6; Zytel 2H Brand of DuPont) (0.01 unit g-mole) was dissolved in 40 ml. of liquid HF. Fluoroxytrifluoromethane (3.6 g.) was passed through the stirred solution over 1 hour, while it was being irradiated by ultraviolet light and cooled in a dry ice-acetone bath at about 78 C. After 15 min. more ultraviolet irradiation, the cooling bath was removed and the solvent was evaporated (by a stream of nitrogen). To the residue, 15 ml. of methanol was added, then pyridine was added to neutrality (check by wet pH paper). The snowwhite, solid precipitate, after drying in vacuo, weighed 0.95 g. and according to F analysis, it contained 17.3 percent fluorine (about 1.25 atom F per unit-mole).

In another experiment, Nylon-6 was subjected to similar fluorinating conditions, with the difference being that 9.5 g. of fluoroxytrifluoromethane was employed (passed in 2 /2 hours), followed by a further 40 min. of ultraviolet irradiation. By an isolation procedure similar to that described in Example 43, 1.5 g. of a snowwhite polymer was obtained, containing 2.9 atoms of F per unit mole.

EXAMPLE 44 Fluorination of Acetic Acid Acetic acid (1.2 g., 0.02 mole) is dissolved in 40 ml. of fluorotrichloromethane, then 3.5 g. of fluoroxytrifluoromethane is passed in during a 2 hour period under ultraviolet irradiation and stirring in a dry-ice acetone bath. After 1 hour more ultraviolet irradiation under similar conditions, the solvent is distilled off and residue is distilled through a micro fractionating column of the spinning'band type, to give 1.1 g. of monofluoroacetic acid, b.p. 1649- C.

Under substantially similar conditions as described in Example 44, but employing 6.5 g. of fluoroxytrifluoromethane during a 3% hour period, followed by another hour of ultraviolet irradiation, difluoroacetic is obtained as the main product.

Employing the procedure of Example 44, but with 10 g. of fluoroxytrifluoromethane passed in during 5 hours, a 3:1 mixture of trifluoroacetic acid and difluoroacetic acid is obtained.

EXAMPLE 45 Fluorination of isobutyric acid Into a solution of isobutyric acid (2.65 g., 0.03 mole) in 50 ml. of fluorotrichloromethane, 1.9 g. (0.0188 mole), of fluoroxytrifluoromethane gas was passed in 3/4 hour, with stirring under ultraviolet light and while being cooled in dry-ice-acetone bath. After further ultraviolet irradiation for another hour at 78 C., the solvent was removed by distillation and the residue was distilled at 2.5 mm Hg pressure. After a small forerun, 1.4 g. of colorless distillate was collected at 6085 C. According to nmr spectrum and elementary analysis, it was a mixture of some isobutyric acid, 2-fluoroisobutyric acid and 3-fluoroisobutyric acid.

Employing the procedure substantially as described in Examples 44 and 45, but substituting for the carboxylic acid used therein equivalent amounts of the carboxylic acids described in Table IV, there are produced the fluorinated carboxylic acids, also described in Table IV.

TABLE IV Example I Starting Material Product 46 Butyric acid 3- and 4-fluor0butyric acid 47 Valerie acid 4- and S-fluorovaleric acid 48 Stearic acid Hexafluoro stearic acid 49 Laurie acid" Tetrafluoro lauric acid 'by increasing amount of reagent and reaction time EXAMPLE 50 Fluorination of Chloroform Into a solution of chloroform (1.20 g., 0.01 mole) dissolved in 35 ml. of dichlorodifluoromethane, fluoroxytrifluoromethane gas (3 g.) is passed in during a period of 4 hours, while being ultraviolet irradiated and stirred, under cooling in a dry ice-acetone bath. By preparative glc, 0.95 g. of fluorotrichloromethane (FREON l l) is isolated from the reaction product.

Employing the procedure of Example 50, but substituting for the chloroform used, therein, the haloalkanes described in Table V, there are produced the fluorinated haloalkanes also described in Table V.

Fluorination of Polyethylene Polyethylene powder was suspended in fluorotrichloromethane and exposed to ultraviolet light. Concurrently a slow stream of fluoroxytrifluorornethane gas was passed through under vigorous stirring, the reactor being immersed in a dry-ice acetone bath. After 2 hours of reaction time, the product was isolated by filtration, then dried. Fluorine analysis indicated 3.1 percent F content in the product. The fluoropolyethylene thus obtained was characterized by substantially greater resistance against chemicals, as compared to the starting material, thus indicating the formation of a thin layer of fluorinated polymer on the surface of the particles.

EXAMPLE 5 8 Fluorination of Polystyrene Polystyrene film (1/2 X 2 inch pieces) is exposed to fluoroxytrifluoromethane under ultraviolet irradiation at -78 C. After 1 hour reaction time a polystyrene polymer with 2.45 percent P content is obtained. The material thus obtained exhibits greatly enhanced stability against chemicals, thus revealing the formation of a thin layer of fluorinated material on its surface.

EXAMPLE 59 Fluorination of Piperidine Piperidine'HCl (6.1 g., 0.05 mole) was dissolved in 60 ml. of liquid hydrofluoric acid. Under stirring and irradiating at 78 C. with an x-ray source, fluoroxytrifluoromethane gas (7.5 g.) was passed in during a 2 9% hour period. After evaporation of the liquid hydrofluoric acid a mixture of piperidine HF salt and fluoropiperidine -HF salt was obtained as a colorless solid.

EXAMPLE 60 4-( 2-Phenyl-l ,1,2,2-tetrafluoroethyl )-a,adimethylbenylamine 4-Brom0stilbene was reduced by standard procedure to 4-bromobibenzyl. In a nitrogen atmosphere 0.0205 g. atom of magnesium turnings were covered with 5 ml. of absolute ether; a crystal of iodine and a few ml. of

a solution of 0.0183 mole of 4-bromobibenzyl in 30 ml. of absolute ether were added. The Grignard reaction started after the mixture was heated to refluxing as the iodine color faded and the solution became cloudy. The remaining solution of the bromide was added rapidly dropwise and the mixture was stirred at reflux for 3 hr. During this period, a solution of 200 mg. of ethylene bromide in 0.5 ml. of ether was added in several portions in order to keep the magnesium clean. At the end of this period, almost all of the magnesium had reacted and a Gilmans test for Grignard reagent was strongly positive. The mixture was cooled in ice and a solution of 2.5 g. (0.04 mole) of acetone in 5 ml. of absolute ether was added rapidly dropwise. After stirring for 1 hr. at room temperature and 30 min. at reflux, the mixture was again cooled in ice and hydrolyzed by the dropwise addition of 2 ml. of water. The yellow ethereal solution was decanted from the gelatinous precipitate that then was re-extracted twice with ether. Evaporation of the combined washed and dried ethereal extracts under reduced pressure left the crude product as a viscous yellow oil. Purification was effected by chromatography on 210 g. of silica gel (Baker, 60-200 mesh powder for chromatography), eluting with chloroform. Evaporation of the solvent under reduced pres sure gave 4-(2-phenethyl)phenylpropanol-2.

Glacial acetic acid, 3.7 ml., was stirred, cooled in an ice-bath until it was about half frozen, and 0.7 g. (0.014 mole) of sodium cyanide was added in small portions, keeping the temperature at 15 20 C. An ice-cold solution of 3.45 g. of concentrated sulfuric acid in 1.8 ml. of glacial acetic acid was added in portions, keeping the temperature at 20 C. by cooling in the ice-bath. The ice-bath then was removed and 0.0112 mole of 4-(2- phenethyl)phenylpropanol-Z was added in portions over 15 min. After stirring for 2 hr. at room temperature and 1 hr. at 30-35 C., the mixture was allowed to stand overnight at room temperature. The mixture was poured into ice and water, neutralized with solid sodium carbonate, and the product was extracted into ether. Evaporation of the washed and dried ethereal extract under reduced pressure left a mixture of products as an off-white solid. Separation was effected by chromatography on 200 g. of silica gel (Baker) eluting with chloroform followed by methanol. Fractions eluted with methanol were combined and the solvent evaporated under reduced pressure to yield a,a-dimethyl-N- formyl4-phenethylbenzylamine.

A solution of 0.0064 mole of a,a-dimethyl-N-formyl- 4-phenethyl-benzylamine in 50 ml. of glacial acetic acid, 35 ml. of water, and 5 ml. of concentrated hydrochloric acid was heated to refluxing for 4 hr. Evaporation of solvents under reduced pressure left a pale brown solid residue that was dissolved in 35 ml. of absolute ethanol. The solution was decolorized with charcoal, filtered, and diluted with 200 ml. of absolute ether causing crystallization of 4-(2-phenethyl)-a,adimethylbenzylamine.HCl.

4-( 2-Phenylethyl )-a,a-dimethylbenzylamine (6.70 g., 0.02 mole) and 50 ml. of anhydrous hydrogen fluoride are cooled to -78 C. in a dry ice-acetone bath. Then under stirring and ultraviolet irradiation, 1 g. of fluoroxytrifluoromethane is added over a period of 30 min. After 30 minutes more, an additional 1 g. of fluoroxytrifluoromethane is added as before. After a total of five such additions of reagent, the cold bath is removed and hydrogen fluoride and excess reagent is uid state in the presence of a free radical initiator.

2. The process of claim 1, wherein the free radical initiator is ionizing radiation.

3. The process of claim 1, wherein the free radical initiator is light.

4. The process of claim 1, wherein the reagent is a fluoroxyperfluoroalkane of l-5 carbon atoms.

5. The process of claim 1, wherein the reaction is conducted in a solvent inert to fluorination.

6. The process of claim 1, wherein the free radical initiator is a chemical chain initiator. 

1. A PROCESS FOR THE PREPARATION OF 3-FLUORO-D-ALANINE AND SALTS THEREOF WHICH COMPRISES THE TREATMENT OF D-ALANINE WITH A REGENT SELECTED FROM THE GROUP CONSISTING OF A FLUOROXYPERFLUOROALKANE OR 1-5 CARBON ATOMS AND FLUOROXYPENTFLUOROSULFUR IN THE LIQUID STATE IN THE PRESENCE OF A FREE RADICAL INITIATOR.
 2. The process of claim 1, wherein the free radical initiator is ionizing radiation.
 3. The process of claim 1, wherein the free radical initiator is light.
 4. The process of claim 1, wherein the reagent is a fluoroxyperfluoroalkane of 1-5 carbon atoms.
 5. The process of claim 1, wherein the reaction is conducted in a solvent inert to fluorination.
 6. The process of claim 1, wherein the free radical initiator is a chemical chain initiator. 